Natural product inhibitors of fatty acid biosynthesis: synthesis of the marine microbial metabolites pseudopyronines A and B and evaluation of their anti-infective activities

Article abstract of DOI:10.1016/j.tet.2007.11.075

Total syntheses of the title natural products, pseudopyronines A (1) and B (2), have been achieved using methyl β-oxo carboxylic ester starting materials. The natural products and a small set of structurally related compounds were evaluated for growth inh

Full text of DOI:10.1016/j.tet.2007.11.075

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1242e1249
www.elsevier.com/locate/tet
Natural product inhibitors of fatty acid biosynthesis: synthesis of the
marine microbial metabolites pseudopyronines A and B and evaluation
of their anti-infective activities
Anna C. Giddens a, Lone Nielsen a,y, Helena I. Boshoff b, Deniz Tasdemir c, Remo Perozzo d,
Marcel Kaiser e, Feng Wang f, James C. Sacchettini f, Brent R. Copp a,
*
a Department of Chemistry, The University of Auckland, Private Bag 92019, Auckland, New Zealand
b Tuberculosis Research Section, LCID, NIAID, NIH, Bethesda, MD 20892, USA
c Centre for Pharmacognosy and Phytotherapy, University of London, London WC1N 1AX, United Kingdom
d School of Pharmaceutical Sciences, University of Geneva, 1211 Geneva 4, Switzerland
e Swiss Tropical Institute, 4002 Basel, Switzerland
f Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA
Received 23 August 2007; received in revised form 5 November 2007; accepted 22 November 2007
Available online 24 November 2007
Abstract
Total syntheses of the title natural products, pseudopyronines A (1) and B (2), have been achieved using methyl b-oxo carboxylic ester start-
ing materials. The natural products and a small set of structurally related compounds were evaluated for growth inhibitory activity against a range
of pathogenic microorganisms and were found to exhibit good potency (IC50ꢀ0.46 mg/mL) and selectivity towards Leishmania donovani.
Several of the compounds inhibited recombinant fatty acid biosynthesis enzymes from both Plasmodium falciparum and Mycobacterium
tuberculosis, validating these targets in the search for new anti-infective agents.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Fatty acid biosynthesis; Marine natural product; Leishmania; Mycobacterium
1. Introduction
protozoa.1,2 The lack of homology between mammalian FAS-I
and bacterial FAS-II systems makes it possible to discover and
develop specific inhibitors that have therapeutic potential in
the treatment of a number of diseases.3
Fatty acids play crucial roles in the function and viability of
cells providing components for biological membranes, acting
as chemical messengers and facilitating the storage of energy.
The biosynthesis of fatty acids follows an iterative process of
condensation and elongation of acetate (in the form of malo-
nate), which is undertaken by a sequence of enzymatic steps
either in the context of a single multifunctional protein
(Type I fatty acid synthase) in animals and fungi or a dissocia-
ble multienzyme system (Type II FAS) in plants, bacteria and
A number of small molecule inhibitors of fatty acid biosyn-
thesis (FAB) are known. Triclosan (an antiseptic) and isoniazid
(an antituberculosis drug) both inhibit bacterial enoyl-ACP-
reductase (FabI/InhA), the enzyme responsible for the final
reduction step during FAB. New classes of inhibitors have
been identified by screening synthetic compound libraries4
and via bioassay guided studies of natural products. Examples
of the latter include cerulenin,5 thiolactomycin6 and more
recently bischloroanthrabenzoxocinone,7 phomallenic acids
AeC,8 platensimycin9 and flavonoids.10,11 The thiolactomycin
scaffold has been the subject of structureeactivity studies, in
particular focussing on growth inhibition of Mycobacterium
* Corresponding author. Tel.: þ64 9 373 7599x88284; fax: þ64 9 373 7422.
E-mail address: b.copp@auckland.ac.nz (B.R. Copp).
y
Present address: Department of Chemistry, University of Aarhus, 8000
Aarhus C, Denmark.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.075

A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
1243
tuberculosis.12 The presence of Type II fatty acid biosynthesis
in the apicoplast of Plasmodium falciparum raises the possibil-
ity of FAB inhibitors also being useful templates for the
discovery of antimalarial agents.13,14 Studies involving
thiolactomycin,15 triclosan16 and flavonoid10 derivatives have
been reported.
exhibited spectroscopic data identical to those reported for
the natural product.18 The synthesis of pseudopyronine B (2)
started with ester 423 and progressed to pyrone 8 in similar
fashion. Deacylation of 8 by heating at 90 ꢁC in 90% H2SO4
yielded 6-heptyl-4-hydroxy-2-pyrone (9) with subsequent
acylation by hexanoyl chloride in TFA affording the pyrone
skeleton with the appropriate length carbon chain at C-3.
Reduction with NaCNBH3 in THF/aq HCl afforded pseudo-
pyronine B (2). Our sample of 2 exhibited identical spectro-
scopic data to those reported for the natural product18 and
also co-eluted on analytical HPLC with an authentic sample
of pseudopyronine B.
Arising from a search for new inhibitors of bacterial fatty
acid biosynthesis, the 2-pyrone-containing natural products
pseudopyronines A (1) and B (2) were recently reported as
mild antibiotics.17,18 The compounds, detected using a lacZ re-
porter cell-based assay, were isolated from fermentation of Pseu-
domonas sp. F92S91, which was itself isolated from a sponge
collected in Fiji. Pyrone 2 had previously been reported as
Sch 419560, identified from fermentation extracts of Pseudomo-
nas fluorescens.19 Pseudopyronines A and B inhibited the
growth of Gram-positive bacteria, including Bacillus subtilis,
methicillin-resistant Staphylococcus aureus, Moraxella catarrha-
lis and Enterococcus faecium (MIC 1e64 mg/mL) with pseudo-
pyronine B being the more active of the two compounds.
Pseudopyronine B (2) inhibited the cellular uptake and incorpo-
ration of thymidine, uridine and amino acids suggestive of
a mode of action related to the disruption of membrane func-
tion.17 Notably, pseudopyronine B showed neither a mem-
brane-damaging effect on human red blood cells nor caused
haemolysis, indicating selectivity for bacterial membranes.
O
O
O
O
i
R
OMe
R
OH
3 R = C5H11
4 R = C7H15
5 R = C5H11
6 R = C7H15
ii
OH
O
7 R = C5H11
8 R = C7H15
O
OH
R
R
O
C7H15
O
O
iv
9
v
iii
OH
O
O
OH
OH
vi
C5H11
3a
O
2
1
C7H15
O
O
O
O
10
6a
Scheme 1. Reagents and conditions: (i) NaOMe, MeOH, H2O, rt; (ii) 1,10-car-
bonyldiimidazole, THF, rt, 24 h; (iii) NaCNBH3, THF, 2 M HCl, rt, 2.5 h; (iv)
90% H2SO4, 130 ꢁC, 1 h; (v) hexanoyl chloride, TFA, reflux, 3 h; (vi)
NaCNBH3, THF, 2 M HCl, rt, 19 h.
1
2
As part of our ongoing interest in the potential offered by
natural products to act as leads in the development of new an-
tituberculosis20 and antimalarial agents,10,21 we now report the
synthesis of pseudopyronines A and B, the preparation of
a number of analogues and the results of screening these com-
pounds for activity against whole organisms and purified
recombinant enzymes of the FAB pathway.
The original report of 1 and 2 demonstrated the lack of sta-
bility of 2 in the CDCl3 NMR solvent, with 2 undergoing re-
action with oxygen to form hydroperoxide 11.18 We also
observed similar instability for pseudopyronine A (1), which
converted over 7 days standing in CDCl3 in an NMR tube to
form the analogous 3-peroxy derivative. New NMR signals
were observed at d 5.68 (s, H-5) and d 1.92 (m, 2H-3a) consis-
tent with those reported for the 3-peroxy derivative of pseudo-
pyronine B.18 This instability should not be observed if the
4-hydroxyl group is trapped as the methyl ether. Indeed,
4-O-methyl pseudopyronine A (12), prepared in 53% yield
from 1 by reaction with excess trimethylphosphate, was stable
in CDCl3 for many weeks with no observed degradation.
2. Results and discussion
2.1. Chemistry
2.1.1. Pseudopyronines A and B
While a number of methodologies have been reported for
the preparation of 4-hydroxy-2-pyrones, the carbonyldiimid-
azole-mediated condensation of b-keto carboxylic acids22 was
particularly attractive for the synthesis of the pseudopyronines
as it could also lead to the preparation of a number of related
compounds for structureeactivity studies. In the case of pseu-
dopyronine A (1), the required b-oxo carboxylic acid 5 was
prepared via saponification of the known methyl b-oxo ester
3 (Scheme 1).23 Cyclisation of 5 using 1.1 equiv of carbonyl-
diimidazole in THF afforded the target acylpyrone skeleton 7.
Reduction of the a-acyl group in 7 utilising NaCNBH3 in
O
OMe
OOH
C6H13
C6H13
O
C7H15
O
O
C5H11
O
11
12
2.1.2. Analogues
To be in a position to study aspects of the structureeactivity
requirements of pseudopyronines A and B, the preparation
THF/aq HCl24 afforded pseudopyronine
A
(1), which

1244
A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
OH
OH
O
OH
rhodesiense and Trypanosoma cruzi, and for cytotoxicity
towards the mammalian L6 and P388 cell lines (Table 1).
Pseudopyronines A and B exhibited modest activity towards
M. tuberculosis grown in nutrient deficient GAST media.28
When assayed against M. tuberculosis grown in 7H9 media
significantly less antibiotic activity was observed for all com-
pounds, perhaps as a consequence of nutrient abundance in
this media making the organism less stressed and less suscep-
tible to antibiotic action or the presence of albumin, binding to
which would reduce drug availability. The 3-acyl precursor to
pseudopyronine A (7) was the only pyrone tested that ex-
hibited comparable antimycobacterial activity to the natural
products. In the parasitic assays, the majority of compounds
tested exhibited slightly more potent activity towards L. dono-
vani than towards the other parasites. In general, the com-
pounds appeared to be more toxic towards P388 leukaemia
cells than towards primary mammalian L6 cells. 3-Acylpyr-
ones 7 and 10 were the most active leishmanicidal compounds
detected in the present study (IC50s 0.46 and 0.55 mg/mL, re-
spectively). These compounds exhibited modest selectivity
(therapeutic) indices (IC50 value for cytotoxicity divided by
IC50 value for antiparasitic activity) of up to 10. This was fol-
lowed by compounds 2, 8, 1, 15 and 12, with less potent anti-
leishmanial activities (IC50 values 1.38e3.37 mg/mL), but
higher selectivity indices against mammalian cells. Similar
levels of selectivity were observed for the mono-alkyl
substituted pyrones 9 and 13, which exhibited modest potency
towards L. donovani (IC50 7e13 mg/mL) but with poor or no
C6H13
C5H11
O
O
O
N
H
O
C7H15
C5H11
13
15
14
OH
O
OH
O
C6H13
O
C6H13
C7H15
C5H11
C5H11
O
O
17
16
Figure 1. Analogues prepared.
of a number of related compounds was also undertaken
(Fig. 1).
The known pyrone 1322 was prepared by deacylation of in-
termediate 7 (Scheme 1) using 90% H2SO4 in 43% yield. Con-
version of pyrone 9 to pyridone 14 proceeded smoothly by
reaction with aq NH3 in 50% yield.25 The pseudopyronine A
regioisomer 15 was prepared via triethylsilane reduction of
the known 5-acylpyrone 16,26 and 5-hexyl substituted pseudo-
pyronine B 17 was prepared by a published procedure.27
2.2. Biological evaluation
Pyrones 1, 2, 7e10, 12, 13, 15e17 and pyridone 14 were
initially evaluated for growth inhibition of M. tuberculosis,
P. falciparum, Leishmania donovani, Trypanosoma brucei
Table 1
Summary of biological activities observed for compounds 1, 2, 7e10, 12e17
Compound
M. tuberculosisa
M. tuberculosisb
T. b. rhodesiensec
T. cruzid
L. donovanie
P. falciparumf
P388g
L6h
1
3.125
0.78e1.56
0.78
>20
25
13.09
12.46
12.12
12.88
44.16
10.77
4.15
17.27
12.03
6.61
10.19
>30
6.05
6.35
>30
>30
>30
>30
19.68
2.63
1.38
0.46
2.1
14.89
14.2
16.41
>5
4.7
5.4
23.2
17.9
5.53
41.8
>90
5.58
57.5
>90
>90
82.6
>90
53.8
2
7
5
1.9
3.3
8
Insoli
12.5
Insoli
n.t.j
Insoli
50
9
10
6.77
0.55
3.37
13.5
>30
3.3
>50
17.37
3.1
>25
3.1
Insoli
12.5
12
13
7.1
6.25
12.5
>50
>50
>50
>50
>50
0.01
50.77
11.6
>5
>5
>25
>25
>25
11.4
9.3
14
15
6.25
12.5
14.73
28.88
11.34
>5
>5
16
17
9.0
11.18
>50
0.01
>5
Isoniazid
Melarsoprol
Benznidazole
Miltefosine
Chloroquine
Mitomycin C
Podophyllotoxin
a
0.003
0.28
0.15
0.043
0.18
0.006
Mycobacterium tuberculosis H37Rv grown in GAST medium. MIC (mg/mL).
Mycobacterium tuberculosis H37Rv grown in 7H9 medium. MIC (mg/mL).
b
c
d
e
f
Trypanosoma brucei rhodesiense (strain STIB 900), trypomastigote stage. IC50 (mg/mL).
Trypanosoma cruzi (strain Tulahuen C4), amastigote stage. IC50 (mg/mL).
Leishmania donovani (strain MHOM-ET-67/L82), amastigote/axenic stage. IC50 (mg/mL).
Plasmodium falciparum (strain K1), IEF stage. IC50 (mg/mL).
P388 murine leukaemia cell line. IC50 (mg/mL).
g
h
i
L6 rat skeletal myoblast cell line. IC50 (mg/mL).
Insoluble in media.
Not tested.
j

A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
1245
Table 2
In vitro activity of compounds 1, 2, 7e10, 12e17 against fatty acid biosynthe-
sis enzymes PfFabG, PfFabI, PfFabZ and InhA
a methodology based upon the condensation of b-oxo carboxy-
lic acids. We have shown that the natural products and a small
set of structurally related compounds exhibit good potency and
reasonable selectivity against a panel of parasitic protozoa, in
particular towards L. donovani. Several of the compounds, in-
cluding the natural products 1 and 2, were found to inhibit the
FAB enzymes PfFabG (b-ketoacyl-ACP-reductase), PfFabI
(enoyl-ACP-reductase) and InhA (enoyl-ACP-reductase) and
thereby inhibit the growth of P. falciparum and M. tuberculo-
sis. These results provide further validation of fatty acid bio-
synthesis as a target for the discovery of new anti-infective
agents.
Compound
PfFabGa
PfFabIa
PfFabZa
InhAb
1
>100
12.8
>100
n.t.c
28.4
>50
n.t.
12
>100
>100
100
n.t.
35%
61% (3.8)
37%
2
4
80
7
8
n.t.
>100
>50
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
65% (3.1)
39%
24%
9
100
>100
n.t.
10
12
13
14
15
16
17
a
68% (2.9)
42%
40%
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
n.t.
12%
47%
4. Experimental section
n.t.
n.t.
43%
IC50 (mg/mL).
Percentage inhibition at 10 mM drug dose or IC50 (mg/mL) in parenthesis.
Not tested.
b
c
4.1. General methods (chemistry)
All reagents were used as supplied. Tetrahydrofuran was
dried over sodium wire. All solvents were distilled prior to
use. Analytical thin layer chromatography was carried out
on Merck DC-plastikfolien Kieselgel 60 F254 plates and prod-
ucts were visualised by UV fluorescence. Flash column chro-
matography was performed using Merck 40e63 mm silica gel.
Mass spectra were recorded on a VG-70SE mass spectrometer.
High-resolution mass spectra were recorded at a nominal
resolution of 5000. Infrared spectra were recorded on a Perkine
Elmer 1600 FTIR spectrophotometer, with all samples exam-
ined as films on a KBr disk. Melting points were measured
on an Electrothermal melting point apparatus and are uncor-
rected. Analytical reversed phase HPLC was run on a Waters
600 HPLC photodiode array system using an Alltech RocketÔ
C18 column (3 mm Econosphere, 33ꢂ7 mm) and eluting with
a linear gradient of H2O (0.05% TFA) through to MeCN.
NMR spectra were recorded at 298 K at either 300 or
400 MHz for 1H and 75 or 100 MHz for 13C on Bruker Avance
300 or 400 spectrometers. Chemical shifts are given in parts
per million on the d scale referenced to the residual solvent
cytotoxicity at the highest test concentrations. While all com-
pounds showed some antitrypanosomal activity against Afri-
can T. brucei rhodesiense, only half of the tested compounds
were active towards American T. cruzi. Compound 12 ap-
peared to be the most promising trypanocidal agent as it in-
hibited both Trypanosoma species with IC50 values of 4.15
and 6.35 mg/mL.
A selection of the available pyrones (1, 2, 7, 9, 10) were
evaluated for their ability to inhibit the function of three re-
combinant enzymes (PfFabG, PfFabI and PfFabZ) of P. falci-
parum fatty acid biosynthesis while the full set of compounds
were evaluated against one enzyme from M. tuberculosis
(InhA¼MtFabI) (Table 2). Both natural products 1 and 2
inhibited PfFabI, the enoyl-ACP-reductase of P. falciparum
with modest IC50s of 12 and 4 mg/mL, respectively. Pseudo-
pyronine B (2) and pyrone 9 inhibited PfFabG, a b-ketoacyl-
ACP-reductase, while none of the compounds tested inhibited
PfFabZ (b-hydroxyacyl-ACP-dehydratase). The enzyme in-
hibitory activities of compounds 1 and 2 were well correlated
with their in vitro growth inhibitory potential on P. falciparum
whole cells, providing evidence that the PfFab pathway may
be the potential cellular target of these compounds. The anti-
malarial activity of compound 7, however, is possibly off-tar-
get, as the IC50 values for PfFabI and PfFabZ enzymes are
much higher in comparison to its antiplasmodial activity.
Compound 9 appeared to be less potent against PfFabG and
PfFabZ enzymes and it was less efficacious against cultured
parasites. The natural product pseudopyronine B (2) and the
methyl ether of pseudopyronine A (12) exhibited activity
against the InhA enzyme with IC50 values of 3.8 and 2.9 mg/
mL, respectively. There was no apparent correlation, however,
between the ability to inhibit the InhA enzyme and whole or-
ganism (M. tuberculosis) activity for most of the remaining
synthetic compounds.
peaks (CHCl3: 1H 7.25, 13C 77.0 ppm; DMSO-d6: 1H 2.50, 13
C
39.4 ppm; MeOH-d4: H 3.30, 13C 49.0 ppm). Assignments
were aided by DEPT135, HSQC and HMBC experiments. Mi-
croanalyses were carried out by the Campbell Laboratory,
University of Otago, Dunedin, New Zealand.
1
Pyrones 16 and 17 were prepared by the literature
methods.26,27
4.1.1. 3-Oxo-octanoic acid (5)
Methyl 3-oxo-octanoate23 (1.12 g, 6.50 mmol) and sodium
methoxide (0.457 g, 8.46 mmol) were dissolved in methanol
(17 mL). Water (17 mL) was added and the mixture left stir-
ring for 18 h at room temperature. Methanol and water were
removed under reduced pressure to give an orange oil. HCl
(10%, v/v, 15 mL) was added and a yellow precipitate formed.
Dichloromethane (30 mL) was added and the precipitate dis-
solved to give a yellow solution. The aqueous phase was ex-
tracted with dichloromethane (2ꢂ20 mL). The combined
organic phases were washed with water (2ꢂ15 mL), dried
over anhydrous magnesium sulfate and the solvent removed
3. Conclusion
The 3,6-dialkyl-4-hydroxy-2-pyrone marine metabolites
pseudopyronines A and B have been synthesized via

1246
A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
in vacuo. The crude solid was washed with hexane (2ꢂ15 mL)
to give 5 as a keto/enol* (4.2:1) mixture (yellow solid;
0.513 g, 50%) (enol NMR resonances are indicated by asterisk).
literature.18 Mp 106e108 ꢁC; analytical HPLC tR 7.11 min;
1
IR nmax 3430, 1634 cmꢃ1; H NMR (400 MHz, MeOH-d4)
d 5.97 (1H, s, H-5), 2.46 (2H, t, J¼7.6 Hz, H-6a), 2.36 (2H,
t, J¼7.4 Hz, H-3a), 1.64 (2H, q, J¼7.4 Hz, H-6b), 1.43 (2H,
m, H-3b), 1.35 (4H, m, H-6c, H-6d), 1.30 (6H, m, H-3c,
H-3d, H-3e), 0.90 (6H, m, H-3f, H-6e); 13C NMR (100 MHz,
MeOH-d4) d 168.8 (quat., C-2), 167.8 (quat., C-4), 165.1
(quat., C-6), 103.9 (quat., C-3), 101.0 (CH, C-5), 34.3 (CH2,
C-6a), 32.9 (CH2, C-3d), 32.2 (CH2, C-6c), 30.2 (CH2,
C-3c), 29.0 (CH2, C-3b), 27.6 (CH2, C-6b), 23.9 (CH2, C-3a),
23.7 (CH2, C-3e), 23.4 (CH2, C-6d), 14.4 (CH3, C-3f), 14.3
Mp 70e72 ꢁC; IR nmax 3420, 1723, 1703 cmꢃ1 1H NMR
;
(300 MHz, CDCl3) d 11.79* (1H, s, OH enolic, 12%), 9.23
(1H, br s, OH), 5.02* (1H, s, H-2 enolic, 12%), 3.50 (2H, s,
H-2, 76%), 2.55 (2H, t, J¼7.4 Hz, H-4, 76%), 2.21* (2H,
t, J¼7.4 Hz, H-4 enolic, 24%), 1.60 (2H, m, H-5), 1.30
(4H, m, H-6, H-7), 0.88 (3H, t, J¼6.9 Hz, H-8); 13C NMR
(75 MHz, CDCl3) d 204.1 (quat., C-3), 182.0* (quat., C-3
enolic), 171.7 (quat., C-1), 88.2* (CH, C-2 enolic), 47.9 (CH2,
C-2), 43.2 (CH2, C-4), 35.3* (CH2, C-4 enolic), 31.1 (CH2,
C-6), 25.9* (CH2, C-5 enolic), 23.1 (CH2, C-5), 22.3
ꢄ
(CH3, C-6e); MS (EI, 70 eV) m/z 266 (Mþ , 18%), 209 (15),
195 (100), 168 (15), 99 (13), 44 (17); HRMS (EI): found
ꢄ
ꢄ
(CH2, C-7), 13.8 (CH3, C-8); MS (EI, 70 eV) m/z 158 (Mþ ,
Mþ , 266.1872. C16H26O3 requires 266.1882.
1%), 114 (15), 71 (22), 58 (100), 43 (100); HRMS (EI): found
ꢄ
Mþ , 158.0943. C8H14O3 requires 158.0943.
4.1.4. 3-Oxo-decanoic acid (6)
Methyl 3-oxo-decanoate (4)23 (7.05 g, 35.2 mmol) and so-
dium methoxide (2.88 g, 53.3 mmol) were dissolved in meth-
anol (100 mL). Water (100 mL) was added and the mixture
left stirring 18 h at room temperature. Methanol and water
were removed in vacuo to give an orange oil. HCl (10%,
v/v, 100 mL) was added and a yellow precipitate formed. Di-
chloromethane (200 mL) was added and the precipitate dis-
solved to give a yellow solution. The aqueous phase was
extracted with dichloromethane (2ꢂ100 mL). The combined
organic phases were washed with water (1ꢂ100 mL), dried
over anhydrous magnesium sulfate and concentrated in vacuo
to give an orange solid. The crude solid was washed with hex-
ane (2ꢂ100 mL) to afford 6 as a keto/enol* (4.4:1) mixture
(yellow solid; 3.22 g, 49%) (enol NMR resonances are indi-
cated by asterisk). Mp 74e75.5 ꢁC (lit.29 mp 76e77 ꢁC); IR
4.1.2. 3-Hexanoyl-4-hydroxy-6-pentyl-2-pyrone (7)
To a stirred solution of 3-oxo-octanoic acid (5) (0.500 g,
3.16 mmol) in dry tetrahydrofuran (6 mL) under nitrogen
at room temperature was added 1,10-carbonyldiimidazole
(0.697 g, 4.30 mmol) in dry tetrahydrofuran (11 mL). The re-
sulting mixture was left stirring at room temperature for 24 h.
The mixture was then acidified to pH 1 with 0.5 M HCl and
extracted with ethyl acetate (60 mL). The organic layer was
washed with brine (1ꢂ60 mL), dried over anhydrous magne-
sium sulfate and solvent removed in vacuo. The crude solid
was recrystallised from methanol to yield 7 as pale yellow
crystals (0.184 g, 21%). Mp 42e43 ꢁC (lit.22 mp 59.5e
1
60 ꢁC); IR nmax 3430, 1720, 1635 cmꢃ1; H NMR (300 MHz,
CDCl3) d 5.90 (1H, s, H-5), 3.05 (2H, t, J¼7.5 Hz, H-3b), 2.46
(2H, t, J¼7.4 Hz, H-6a), 1.65 (4H, m, H-3c, H-6b), 1.33 (8H,
m), 0.89 (6H, t, J¼7.0 Hz, H-3f, H-6e); 13C NMR (75 MHz,
CDCl3) d 208.0 (quat., C-3a), 181.3 (quat., C-4), 172.5
(quat., C-6), 161.1 (quat., C-2), 100.7 (CH, C-5), 99.6 (quat.,
C-3), 41.6 (CH2, C-3b), 34.2 (CH2, C-6a), 31.4 (CH2, C-3d),
31.0 (CH2, C-6c), 26.0 (CH2, C-6b), 23.7 (CH2, C-3c), 22.5
(CH2, C-3e or C-6d), 22.2 (CH2, C-6d or C-3e), 13.9 (CH3,
C-3f or C-6e), 13.8 (CH3, C-3f or C-6e); MS (EI, 70 eV) m/z
1
nmax 3431, 1723, 1702 cmꢃ1; H NMR (400 MHz, CDCl3)
d 11.78* (1H, s, OH enolic, 11%), 5.02* (1H, s, H-2 enolic,
11%), 3.50 (2H, s, H-2, 78%), 2.55 (2H, t, J¼7.6 Hz, H-4,
78%), 2.21* (2H, t, J¼7.6 Hz, H-4 enolic, 22%), 1.57 (2H,
m, H-5), 1.27 (8H, m), 0.86 (3H, t, J¼7.0 Hz, H-10); 13C
NMR (100 MHz, CDCl3) d 204.5 (quat., C-3), 182.2* (quat.,
C-3 enolic), 171.5 (quat., C-1), 88.2* (CH, C-2 enolic), 47.9
(CH2, C-2), 43.3 (CH2, C-4), 35.3* (CH2, C-4 enolic), 31.6
(CH2, C-8), 28.9 (CH2, C-6 or C-7), 28.9 (CH2, C-6 or C-7),
26.2* (CH2, C-5 enolic), 23.4 (CH2, C-5), 22.6 (CH2, C-9),
ꢄ
280 (Mþ , 17%), 237 (98), 224 (100), 209 (90), 168 (68), 99
ꢄ
(35), 69 (32), 43 (73); HRMS (EI): found Mþ , 280.1674.
ꢄ
C16H24O4 requires 280.1675. Anal. Calcd for C16H24O4: C,
68.54; H, 8.63. Found: C, 68.66; H, 8.77.
14.0 (CH3, C-10); MS (EI, 70 eV) m/z 186 (Mþ , 1%), 142
ꢄ
(19), 71 (36), 58 (100), 43 (35); HRMS (EI): found Mþ ,
186.1259. C10H18O3 requires 186.1256.
4.1.3. 3-Hexyl-4-hydroxy-6-pentyl-2-pyrone
(pseudopyronine A) (1)
4.1.5. 6-Heptyl-4-hydroxy-3-octanoyl-2-pyrone (8)
To a stirred solution of acylpyrone 7 (0.100 g, 0.357 mmol)
in tetrahydrofuran (2.1 mL) was added 2 M HCl (1.8 mL). So-
dium cyanoborohydride (0.056 g, 0.891 mmol) was added por-
tionwise to the resulting solution. The mixture was left stirring
at room temperature for 2.5 h. The solvent was then removed
in vacuo, the resulting solid dissolved in dichloromethane
(5 mL) and washed with water (2ꢂ5 mL), dried over anhy-
drous magnesium sulfate, filtered and concentrated in vacuo
to give a yellow solid. Purification by column chromatography
(dichloromethane) afforded 1 as a yellow solid (0.078 g, 82%).
Spectroscopic data agreed with those reported in the
To a stirred solution of 3-oxo-decanoic acid (6) (0.367 g,
1.97 mmol) in dry tetrahydrofuran (4 mL) under nitrogen at
room temperature was added 1,10-carbonyldiimidazole
(0.431 g, 2.66 mmol) in dry tetrahydrofuran (8 mL). The re-
sulting mixture was left stirring at room temperature for
24 h after which time it was acidified to pH 1 with 0.5 M
HCl, and extracted with ethyl acetate (1ꢂ50 mL). The organic
layer was washed with brine (1ꢂ50 mL), dried over anhydrous
magnesium sulfate and concentrated in vacuo to give an or-
ange solid. The crude solid was recrystallised from methanol
to afford 8 as a pale yellow crystals (0.232 g, 35%). Mp

A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
1247
58e59 ꢁC (lit.22 mp 64.5e65 ꢁC); IR nmax 3435, 1727,
(75 MHz, CDCl3) d 208.0 (quat., C-3a), 181.3 (quat., C-4),
172.5 (quat., C-6), 161.1 (quat., C-2), 100.7 (CH, C-5), 99.6
(quat., C-3), 41.6 (CH2, C-3b), 34.3 (CH2, C-6a), 31.6 (CH2,
C-6e), 31.4 (CH2, C-3d), 28.9 (CH2, C-6c), 28.8 (CH2,
C-6d), 26.4 (CH2, C-6b), 23.7 (CH2, C-3c), 22.5 (CH2, C-6f),
22.5 (CH2, C-3e), 14.0 (CH3, C-3f or C-6g), 13.9 (CH3,
1
1639 cmꢃ1; H NMR (300 MHz, CDCl3) d 5.89 (1H, s, H-5),
3.04 (2H, t, J¼7.6 Hz, H-3b), 2.45 (2H, t, J¼7.5 Hz, H-6a),
1.64 (4H, m, H-3c, H-6b), 1.31 (16H, m), 0.86 (6H, m,
H-3h, H-6g); 13C NMR (75 MHz, CDCl3) d 208.0 (quat.,
C-3a), 181.2 (quat., C-4), 172.5 (quat., C-6), 161.0 (quat.,
C-2), 100.7 (CH, C-5), 99.6 (quat., C-3), 41.6 (CH2, C-3b),
34.3 (CH2, C-6a), 31.7 (CH2, C-3f or C-6e), 31.6 (CH2,
C-3f or C-6e), 29.2 (CH2, C-3d or C-3e), 29.1 (CH2, C-3e
or C-3d), 28.9 (CH2, C-6c or C-6d), 28.8 (CH2, C-6d or C-
6c), 26.3 (CH2, C-6b), 24.0 (CH2, C-3c), 22.6 (CH2, C-3g or
C-6f), 22.5 (CH2, C-6f or C-3g), 14.0 (CH3, C-3h), 14.0
ꢄ
C-6g or C-3f); MS (EI, 70 eV) m/z 308 (Mþ , 19%), 265
(100), 252 (95), 237 (73), 168 (54), 69 (25), 43 (64); HRMS
ꢄ
(EI): found Mþ , 308.1994. C18H28O4 requires 308.1988.
Anal. Calcd for C18H28O4: C, 70.10; H, 9.15. Found: C,
70.39; H, 9.23.
ꢄ
(CH3, C-6g); MS (EI, 70 eV) m/z 336 (Mþ , 14%), 265 (85),
4.1.8. 6-Heptyl-3-hexyl-4-hydroxy-2-pyrone
(pseudopyronine B) (2)
To a stirred solution of acylpyrone 10 (0.070 g,
252 (92), 237 (55), 168 (53), 69 (30), 57 (84), 41 (93), 40
ꢄ
(100); HRMS (EI): found Mþ , 336.2300. C20H32O4 requires
336.2301. Anal. Calcd for C20H32O4: C, 71.39; H, 9.59. Found:
C, 71.64; H, 9.75.
0.227 mmol) in tetrahydrofuran (4.6 mL) was added 2 M HCl
(3.7 mL). Sodium cyanoborohydride (0.041 g, 0.652 mmol)
was added portionwise to the resulting solution. The reaction
was monitored by TLC and after 4 h there was mostly starting
material present. More sodium cyanoborohydride (0.040 g,
0.637 mmol) was added and the reaction mixture was left
stirring for 19 h. The solvent was then removed in vacuo and
the resulting solid dissolved in dichloromethane (10 mL).
The organic layer was washed with water (2ꢂ10 mL), dried
over anhydrous magnesium sulfate and concentrated in vacuo
to give a yellow solid. Purification by column chromatography
(dichloromethane) afforded 2 as a pale yellow solid (0.035 g,
52%). Spectroscopic data agreed with those reported in the lit-
erature18 and the product co-eluted on analytical HPLC with
an authentic sample. Mp 84e86 ꢁC; analytical HPLC tR
4.1.6. 6-Heptyl-4-hydroxy-2-pyrone (9)
Sulfuric acid (90%, 6 g) was added to pyrone 8 (0.880 g,
2.62 mmol) and the solution was heated at 130 ꢁC for 1 h.
The reaction mixture was then cooled to room temperature
and a few pieces of ice were added with stirring. The oily resi-
due was extracted with ethyl acetate (3ꢂ20 mL) and the com-
bined organic layers washed with water (3ꢂ20 mL), dried
over anhydrous magnesium sulfate and concentrated in vacuo
to give a brown oil. Purification by column chromatography
(dichloromethane/methanol 9:1) afforded 9 as a yellow solid
(0.379 g, 69%). Mp 72e73 ꢁC (lit.22 mp 71e71.5 ꢁC); Rf
(10% MeOH/CH2Cl2) 0.33; IR nmax 3433, 1646 cmꢃ1 1H
;
NMR (400 MHz, CDCl3) d 5.97 (1H, d, J¼2.0 Hz, H-5),
5.57 (1H, d, J¼2.0 Hz, H-3), 2.47 (2H, t, J¼7.5 Hz, H-6a),
1.63 (2H, q, J¼7.6 Hz, H-6b), 1.27 (8H, m, H-6c-f), 0.86
(3H, m, H-6g); 13C NMR (100 MHz, CDCl3) d 172.6 (quat.,
C-4), 168.4 (quat., C-2), 167.4 (quat., C-6), 101.3 (CH,
C-5), 89.7 (CH, C-3), 33.6 (CH2, C-6a), 31.6 (CH2, C-6e),
28.9 (2ꢂCH2, C-6c, C-6d), 26.6 (CH2, C-6b), 22.6 (CH2,
7.59 min; IR nmax 3429, 1633 cmꢃ1 1H NMR (300 MHz,
;
DMSO-d6) d 10.99 (1H, br s, OH), 5.95 (1H, s, H-5), 2.39
(2H, t, J¼7.5 Hz, H-6a), 2.24 (2H, t, J¼7.7 Hz, H-3a), 1.52
(2H, q, J¼7.0 Hz, H-6b), 1.35 (2H, m, H-3b), 1.27 (14H,
m), 0.84 (6H, m, H-3f, H-6g); 13C NMR (75 MHz, DMSO-
d6) d 164.70 (quat., C-2), 164.68 (quat., C-4), 162.7 (quat,
C-6), 101.3 (quat., C-3), 99.1 (CH, C-5), 32.5 (CH2, C-6a),
31.1 (CH2, C-6e), 31.0 (CH2, C-3d), 28.4 (CH2, C-3c), 28.2
(CH2, C-6d), 28.1 (CH2, C-6c), 27.4 (CH2, C-3b), 26.1
(CH2, C-6b), 22.6 (CH2, C-3a), 22.0 (CH2, C-6f), 21.9 (CH2,
C-3e), 13.81 (CH3, C-6g), 13.78 (CH3, C-3f); MS (EI,
ꢄ
C-6f), 14.0 (CH3, C-6g); MS (EI, 70 eV) m/z 210 (Mþ ,
14%), 139 (34), 126 (100), 111 (78), 98 (44), 84 (78), 69
ꢄ
(77), 41 (41); HRMS (EI): found Mþ , 210.1257. C12H18O3
requires 210.1256.
ꢄ
70 eV) m/z 294 (Mþ , 8%), 224 (35), 195 (15), 55 (74), 53
ꢄ
4.1.7. 6-Heptyl-3-hexanoyl-4-hydroxy-2-pyrone (10)
(81), 43 (100); HRMS (EI): found Mþ , 294.2197. C18H30O3
requires 294.2195.
A mixture of pyrone 9 (0.150 g, 0.713 mmol) and hexanoyl
chloride (0.20 mL, 1.42 mmol) in trifluoroacetic acid (0.5 mL)
was refluxed under nitrogen for 3 h. The mixture was cooled to
room temperature and ice water (1.5 mL) added. The resulting
precipitate was dissolved in dichloromethane (5 mL) and the
solution washed with water (3ꢂ10 mL). The organic layer
was dried over anhydrous magnesium sulfate and concentrated
in vacuo. Purification of the crude solid by column chromato-
graphy (dichloromethane) afforded 10 as a pale yellow solid
(0.143 g, 65%). Mp 63.5e64.5 ꢁC; Rf (33% EtOAc/hexane)
4.1.9. 4-Hydroxy-6-pentyl-2-pyrone (13)
Sulfuric acid (90%, 0.5 g) was added to acylpyrone 7
(0.017 g, 0.061 mmol) and the solution was heated at 130 ꢁC
for 1 h. The reaction mixture was then cooled to room temper-
ature and a few pieces of ice were added with stirring. The oily
residue was extracted with ethyl acetate (3ꢂ5 mL) and the
combined organic layers washed with water (1ꢂ5 mL). The
organic layer was dried over anhydrous magnesium sulfate
and concentrated in vacuo. The crude oil was purified by col-
umn chromatography (dichloromethane/methanol 9:1) to afford
13 as a yellow solid (0.0047 g, 43%). Mp 47e49 ꢁC (lit.22 mp
48.0e50.0 ꢁC); Rf (10% MeOH/CH2Cl2) 0.30; IR nmax 3401,
1
0.74; IR nmax 3432, 1727, 1637 cmꢃ1; H NMR (300 MHz,
CDCl3) d 5.89 (1H, s, H-5), 3.05 (2H, t, J¼7.4 Hz, H-3b),
2.46 (2H, t, J¼7.5 Hz, H-6a), 1.63 (4H, m, H-3c, H-6b), 1.32
(12H, m, H-3def), 0.87 (6H, m, H-3f, H-6g); 13C NMR

1248
A.C. Giddens et al. / Tetrahedron 64 (2008) 1242e1249
1655 cmꢃ1
;
1H NMR (300 MHz, CDCl3) d 5.98 (1H, d,
Anal. Calcd for C12H19NO2$1/6H2O: C, 67.89; H, 9.18; N,
6.60. Found: C, 67.81; H, 9.00; N, 6.62.
J¼2.0 Hz, H-5), 5.57 (1H, d, J¼2.0 Hz, H-3), 2.46 (2H, t,
J¼7.5 Hz, H-6a), 1.63 (2H, q, J¼7.4 Hz, H-6b), 1.30 (4H,
m, H-6c, H-6d), 0.87 (3H, m, H-6e); 13C NMR (75 MHz,
CDCl3) d 172.6 (quat., C-4), 168.3 (quat., C-2), 167.4 (quat.,
C-6), 101.3 (CH, C-5), 89.8 (CH, C-3), 33.6 (CH2, C-6a),
31.0 (CH2, C-6c), 26.3 (CH2, C-6b), 22.3 (CH2, C-6d), 13.8
(CH3, C-6e); MS m/z (EI, 70 eV) m/z 182 (Mþ , 27%), 126
(100), 111 (89), 98 (48), 84 (79), 69 (89), 43 (36); HRMS
(EI): found Mþ , 182.0942. C10H14O3 requires 182.0943.
4.1.12. 5-Hexyl-4-hydroxy-6-pentyl-2-pyrone (15)
5-Hexanoyl-4-hydroxy-6-pentyl-2-pyrone (16)26 (0.050 g,
0.178 mmol), triethylsilane (0.125 mL, 0.774 mmol) and
LiClO4 (0.2 mg, 0.00188 mmol) were dissolved in TFA
(1.2 mL) and left stirring at room temperature for 23 h. The
solvent was removed in vacuo to give an orange oil. Purifica-
tion by column chromatography (dichloromethane/methanol
9.5:0.5) afforded 15 as a yellow solid (0.034 g, 71%). Mp
71.5e73 ꢁC; Rf (10% MeOH/CH2Cl2) 0.38; IR nmax 3444,
ꢄ
ꢄ
4.1.10. 3-Hexyl-4-methoxy-6-pentyl-2-pyrone (12)
1
1704, 1639 cmꢃ1; H NMR (400 MHz, CDCl3) d 11.40 (1H,
Trimethylphosphate (0.5 mL, 4.25 mmol) was added to
pseudopyronine A (1) (0.030 g, 0.113 mmol) and potassium
carbonate (0.019 g, 0.135 mmol) and the resulting mixture
was heated at 140 ꢁC, under nitrogen, for 2 h. The mixture
was then cooled to room temperature, diluted with water
(5 mL) and extracted with ethyl acetate (4ꢂ3 mL). The com-
bined organic layers were dried over anhydrous magnesium
sulfate and concentrated in vacuo to give an orange oil. Puri-
fication by column chromatography (hexane/ethyl acetate 3:1)
afforded 12 as a yellow oil (0.017 g, 53%). Rf (CH2Cl2) 0.56;
br s, OH), 5.66 (1H, s, H-3), 2.50 (2H, t, J¼7.6 Hz, H-6a),
2.35 (2H, t, J¼7.5 Hz, H-5a), 1.63 (2H, q, J¼7.4 Hz, H-6b),
1.43 (2H, m, H-5b), 1.31 (10H, m), 0.87 (6H, m, H-5f,
H-6e); 13C NMR (100 MHz, CDCl3) d 172.7 (quat., C-4),
167.7 (quat., C-2), 163.1 (quat., C-6), 113.5 (quat., C-5),
90.0 (CH, C-3), 31.6 (CH2, C-6c), 31.4 (CH2, C-5d), 30.7
(CH2, C-6a), 29.5 (CH2, C-5b), 29.2 (CH2, C-5c), 27.2 (CH2,
C-6b), 24.2 (CH2, C-5a), 22.6 (CH2, C-6d), 22.3 (CH2,
C-5e), 14.0 (CH3, C-5f or C-6e), 13.9 (CH3, C-6e or C-5f);
ꢄ
MS (EI, 70 eV) m/z 266 (Mþ , 12%), 223 (24), 195 (100),
1
IR nmax 1644 cmꢃ1; H NMR (400 MHz, CDCl3) d 5.95 (1H,
ꢄ
153 (30), 99 (29), 71 (18), 43 (58); HRMS (EI): found Mþ ,
s, H-5), 3.84 (3H, s, OCH3), 2.45 (2H, t, J¼7.6 Hz, H-6a), 2.37
(2H, t, J¼7.6 Hz, H-3a), 1.65 (2H, q, J¼7.6 Hz, H-6b), 1.40
(2H, m, H-3b), 1.29 (10H, m), 0.87 (6H, m, H-3f, H-6e);
13C NMR (100 MHz, CDCl3) d 165.8 (quat., C-4), 165.6
(quat., C-2), 164.7 (quat., C-6), 105.8 (quat., C-3), 94.1 (CH,
C-5), 56.1 (CH3, OCH3), 34.2 (CH2, C-6a), 31.7 (CH2, C-
3d), 31.2 (CH2, C-6c), 29.2 (CH2, C-3c), 28.0 (CH2, C-3b),
26.7 (CH2, C-6b), 23.3 (CH2, C-3a), 22.6 (CH2, C-3e), 22.3
(CH2, C-6d), 14.1 (CH3, C-3f), 13.9 (CH3, C-6e); MS (EI,
266.1880. C16H26O3 requires 266.1882. Anal. Calcd for
C16H26O3: C, 72.14; H, 9.84. Found: C, 72.32; H, 9.81.
4.2. General methods (biological assays)
Details of the whole organism parasite30,31 and M. tubercu-
losis20 and purified enzyme10,31,32 biological assay protocols
have been reported elsewhere.
ꢄ
70 eV) m/z 280 (Mþ , 7%), 210 (48), 209 (100), 181 (16),
ꢄ
Acknowledgements
43 (13); HRMS (EI): found Mþ , 280.2033. C17H28O3 requires
280.2038.
The authors wish to thank Drs. Fanming Kong and Guy
Carter (Wyeth Research) for an authentic sample of pseudo-
pyronine B. A.C.G. thanks the University of Auckland for
a doctoral scholarship. This investigation received financial
support from the UNICEF/UNDP/World Bank/WHO Special
Programme for Research and Training in Tropical Diseases
(TDR). J.C.S. acknowledges support from the Robert A.
Welch Foundation.
4.1.11. 6-Heptyl-4-hydroxy-2-pyridone (14)
Ammonia (28%, 2 mL) was added to 6-heptyl-4-hydroxy-
2-pyrone (9) (0.10 g, 0.476 mmol) and the solution heated at
100 ꢁC for 6 h. The reaction was diluted with water (4 mL)
and cooled to room temperature. The resulting solid was fil-
tered and dried in vacuo. Purification by column chromatogra-
phy (dichloromethane/methanol 9:1) afforded 14 as a pale
brown solid (0.050 g, 50%). Mp 255e257 ꢁC; Rf (10%
References and notes
MeOH/CH2Cl2) 0.27; IR nmax 3268, 3106, 1633 cmꢃ1 1H
;
NMR (300 MHz, DMSO-d6) d 10.86 (1H, br s), 10.31 (1H,
br s), 5.58 (1H, d, J¼2.0 Hz, H-5), 5.33 (1H, d, J¼2.1 Hz,
H-3), 2.33 (2H, t, J¼7.8 Hz, H-6a), 1.51 (2H, q, J¼6.6 Hz,
H-6b), 1.24 (8H, br s, H-6cef), 0.85 (3H, m, H-6g); 13C
NMR (75 MHz, DMSO-d6) d 167.4 (quat., C-4 or C-2),
164.7 (quat., C-2 or C-4), 150.0 (quat., C-6), 97.2 (CH, C-5),
95.8 (CH, C-3), 32.0 (CH2, C-6a), 31.0 (CH2, C-6e), 28.2
(2ꢂCH2, C-6c, C-6b), 27.9 (CH2, C-6b), 21.9 (CH2, C-6f),
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Newlander, K. A.; Burgess, W. J.; DeWolf, W. E.; Elkins, P. A.; Head,
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(12), 138 (48), 125 (100), 97 (16), 69 (11), 41 (13); HRMS
ꢄ
(EI): found Mþ , 209.1412. C12H19NO2 requires 209.1416.

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